Abstract
Intrauterine inflammation impacts prenatal neurodevelopment and is linked to adverse neurobehavioral outcomes ranging from cerebral palsy to autism spectrum disorder. However, the mechanism by which a prenatal exposure to intrauterine inflammation contributes to life-long neurobehavioral consequences is unknown. To address this gap in knowledge, this study investigates how inflammation transverses across multiple anatomic compartments from the maternal reproductive tract to the fetal brain and what specific cell types in the fetal brain may cause long-term neuronal injury. Utilizing a well-established mouse model, we found that mid-gestation intrauterine inflammation resulted in a lasting neutrophil influx to the decidua in the absence of maternal systemic inflammation. Fetal immunologic changes were observed at 72-hours post-intrauterine inflammation, including elevated neutrophils and macrophages in the fetal liver, and increased granulocytes and activated microglia in the fetal brain. Through unbiased clustering, a population of Gr-1+ γ/δ T cells was identified as the earliest immune cell shift in the fetal brain of fetuses exposed to intrauterine inflammation and determined to be producing high levels of IFNγ when compared to γ/δ T cells in other compartments. In a case-control study of term infants, IFNγ was found to be elevated in the cord blood of term infants exposed to intrauterine inflammation compared to those without this exposure. Collectively, these data identify a novel cellular immune mechanism for fetal brain injury in the setting of intrauterine inflammation.
Highlights
Maternal inflammation is associated with fetal brain injury and long-term neurodevelopmental impairment
Our previous work utilizing our model of intrauterine inflammation (IUI) has demonstrated minimal maternal immune activation after IUI, noted by a lack of maternal serum cytokine elevation [17]
The developing brain is exquisitely sensitive to intrauterine inflammation (IUI) such that the inflammatory insult may be asymptomatic in the mother but may cause long-lasting neuronal damage in the fetus
Summary
Maternal inflammation is associated with fetal brain injury and long-term neurodevelopmental impairment. Patients with ASD have greater T cell infiltration at the blood brain barrier in post-mortem studies [11]. These two distant immunologic findings – in utero and postmortem – outline the wide knowledge gap in the actual pathogenesis of these disorders. Neuroimmune “education” may occur prenatally; for example, one mouse model of ASD is initiated by injections of IL-17A to the fetal brain [14]. This model does not address how subclinical intrauterine inflammation could be transmitted across the maternal-fetal dyad and induce fetal brain injury
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